Efficacy and Safety of Quarter-Dose Blood Pressure–Lowering Agents

A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background

Control of hypertension is suboptimal, since only 1 in 3 individuals on treatment achieve their blood pressure (BP) targets [1,2]. Studies suggest that low-dose combinations of antihypertensive medications may provide the best balance between side effects and BP reduction, because at low doses most side effects are avoided and most benefit is realized, which may be particularly true for combinations containing quarter doses of several BP-lowering agents [3-5].

In this systematic review of randomized trials, the potential clinical role of quarter-dose monotherapy and combination therapy was assessed. For this, randomized controlled trials (either parallel or crossover) with a treatment and follow-up of at least two weeks were included in the analysis, only if there were efficacy or safety data that were measured for at least 1 of the 5 major classes of BP–lowering medications: calcium channel blockers, β-blockers, ARBs, ACEis, and thiazide diuretics. Studies were only considered when at least one arm was allocated quarter-dose therapy (with one or multiple agents) and at least one arm allocated placebo or standard-dose monotherapy. Up-titration studies must have had BP or safety data for at least the first two weeks before titration occurred.

Main results

A total of 42 studies were included in the meta-analysis, with 20,284 participants who had a mean age of 54 years and a mean baseline BP of 154/101 mmHg.

The efficacy in BP-lowering of single quarter-dose therapy versus placebo, which was assessed in 4721 participants in 36 trials, showed that single quarter-dose therapy reduced systolic BP (SBP) by −4.7 (95% CI −5.4 to −3.9) and diastolic (DBP) by −2.4 mmHg (95% CI −2.8 to −1.9).

Compared with placebo, there was no significant difference in risk of adverse events in single quarter-dose comparisons or dual quarter-dose comparisons, or the quadruple quarter-dose placebo comparison.

No individual medication class was associated with a greater risk of adverse events compared with placebo.

Conclusion

In a meta-analysis of 42 randomized studies, dual quarter-dose combinations of BP-lowering agents were as effective as standard-dose monotherapy with fewer side effects. Moreover, a quadruple quarter-dose combination treatment was twice as efficacious as standard-dose monotherapy. Quarter-dose combinations could improve the efficacy and tolerability of BP–lowering therapy.

Editorial comment

In their editorial article [6], Grassi and Mancia emphasize the unmet medical need for more effective BP-lowering therapies: ‘…BP control may not be easily achievable even when optimal treatment is used, as exemplified by the frequent inability to meet this goal also in randomized trials despite large use of combination treatment and environmental conditions that minimize therapeutic inertia and maximize treatment adherence.’

They also discuss the limitations of the meta-analysis of Bennet et al:

the quadruple quarter dose combination treatment results are based on a single study with a small sample size

the on-treatment duration was on average short

there are no data on the effects of a quarter dose triple combination

The authors conclude: ‘Finally, it would be important to expand the information provided by the meta-analysis of Bennett et al to ambulatory or home BP to see whether the remarkable ability of the quarter dose combination treatment to lower BP is consistent over the 24 hours or the low dose attenuates the effect at times farther from the drug administration or in conditions in which treatment has to successfully oppose the effect of pressure influences. These limitations, however, do not detract from the interest of the study data and their favourable clinical implications.’